Miguel Debono1, Ashwini Mallappa2, Verena Gounden2, Aikaterini A Nella2, Robert F Harrison2, Christopher A Crutchfield2, Peter S Backlund2, Steven J Soldin2, Richard J Ross2, Deborah P Merke3. 1. National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK m.debono@sheffield.ac.uk. 2. National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK. 3. National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Abstract
OBJECTIVES: The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids. DESIGN: This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH. METHODS: Twenty-four-hour serum sampling for ACTH, 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, DHEA, testosterone, progesterone and 24-h urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and maximal (TmaxAC) adrenocortical hormone levels after dose administration was calculated. RESULTS: A significant rhythm was confirmed for ACTH (r(2), 0.95; P<0.001), 17OHP (r(2), 0.70; P=0.003), androstenedione (r(2), 0.47; P=0.043), androsterone (r(2), 0.80; P<0.001), testosterone (r(2), 0.47; P=0.042) and progesterone (r(2), 0.64; P=0.006). The mean (s.d.) TminAC and TmaxAC for 17OHP and A4 were: morning prednisone (4.3 (2.3) and 9.7 (3.5) h), evening prednisone (4.5 (2.0) and 10.3 (2.4) h), and daily dexamethasone (9.2 (3.5) and 16.4 (7.2) h). AUC0-24 h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP. CONCLUSION: In CAH patients, adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.
OBJECTIVES: The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids. DESIGN: This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH. METHODS: Twenty-four-hour serum sampling for ACTH, 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, DHEA, testosterone, progesterone and 24-h urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and maximal (TmaxAC) adrenocortical hormone levels after dose administration was calculated. RESULTS: A significant rhythm was confirmed for ACTH (r(2), 0.95; P<0.001), 17OHP (r(2), 0.70; P=0.003), androstenedione (r(2), 0.47; P=0.043), androsterone (r(2), 0.80; P<0.001), testosterone (r(2), 0.47; P=0.042) and progesterone (r(2), 0.64; P=0.006). The mean (s.d.) TminAC and TmaxAC for 17OHP and A4 were: morning prednisone (4.3 (2.3) and 9.7 (3.5) h), evening prednisone (4.5 (2.0) and 10.3 (2.4) h), and daily dexamethasone (9.2 (3.5) and 16.4 (7.2) h). AUC0-24 h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP. CONCLUSION: In CAH patients, adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.
Authors: Gabriela P Finkielstain; Mimi S Kim; Ninet Sinaii; Miki Nishitani; Carol Van Ryzin; Suvimol C Hill; James C Reynolds; Reem M Hanna; Deborah P Merke Journal: J Clin Endocrinol Metab Date: 2012-09-18 Impact factor: 5.958
Authors: Richard J Auchus; Elizabeth O Buschur; Alice Y Chang; Gary D Hammer; Carole Ramm; David Madrigal; George Wang; Martha Gonzalez; Xu Steven Xu; Johan W Smit; James Jiao; Margaret K Yu Journal: J Clin Endocrinol Metab Date: 2014-04-29 Impact factor: 5.958
Authors: Clemens Kamrath; Ze'ev Hochberg; Michaela F Hartmann; Thomas Remer; Stefan A Wudy Journal: J Clin Endocrinol Metab Date: 2011-12-14 Impact factor: 5.958
Authors: Brian R Stolze; Verena Gounden; Jianghong Gu; Elizabeth A Elliott; Likhona S Masika; Brent S Abel; Deborah P Merke; Monica C Skarulis; Steven J Soldin Journal: J Steroid Biochem Mol Biol Date: 2015-12-22 Impact factor: 4.292
Authors: Phyllis W Speiser; Wiebke Arlt; Richard J Auchus; Laurence S Baskin; Gerard S Conway; Deborah P Merke; Heino F L Meyer-Bahlburg; Walter L Miller; M Hassan Murad; Sharon E Oberfield; Perrin C White Journal: J Clin Endocrinol Metab Date: 2018-11-01 Impact factor: 5.958
Authors: Hedi L Claahsen-van der Grinten; Phyllis W Speiser; S Faisal Ahmed; Wiebke Arlt; Richard J Auchus; Henrik Falhammar; Christa E Flück; Leonardo Guasti; Angela Huebner; Barbara B M Kortmann; Nils Krone; Deborah P Merke; Walter L Miller; Anna Nordenström; Nicole Reisch; David E Sandberg; Nike M M L Stikkelbroeck; Philippe Touraine; Agustini Utari; Stefan A Wudy; Perrin C White Journal: Endocr Rev Date: 2022-01-12 Impact factor: 19.871